Amino acids such as L-glutamic acid, L-aspartic acid are known to be central nerve system neurotransmitters. It is said that extracellular accumulation of these excitatory amino acids and their continuous excessive stimulation of to nerves lead to Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease, senile dementia and neurodegeneration or deficiency in mental and motor functions observed after the condition of cerebral ischemia, oxygen deficiency or hypoglycemia.
In consequence, it has been considered that regulator of the abnormal activity of an excitatory amino acid is useful for the treatment of neurodegeneration and mental diseases, and it is considered also that such a drug will be effective for drug dependence and alcohol dependence.
Excitatory amino acids exhibit their action through glutamate receptors which are specific receptors existing at postsynaptic or presynaptic region. Such receptors are presently classified into the following three groups based on the electrophysiological and neurochemical studies.
1) NMDA (N-methyl-D-aspartate) receptors PA1 2) non-NMDA receptors PA1 3) metabotropic glutamate receptors PA1 R: an imidazolyl group or a di-lower alkylamino group, PA1 R.sup.1 : (1) ahalogen atom, anitro group, a cyano group, a carboxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a lower alkylthio group, a lower alkylsulfinyl or a lower alkylsulfonyl group or a carbamoyl group, PA1 R.sup.2 : a hydroxyl group, a lower alkoxy group, an amino group or a mono- or di-lower alkylamino group, PA1 A: a lower alkylene group which may be substituted or a group represented by a formula --O--B--, and PA1 B: a lower alkylene group, PA1 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 may be the same or different from one another and each represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group, CF.sub.3, a nitro group, a halogen atom, NR.sup.9 R.sup.10, a cyano group, SO.sub.p R.sup.11, SO.sub.2 NR.sup.12 R.sup.13, SO.sub.3 H, a SO.sub.3 C.sub.1 -C.sub.6 alkyl group or OR.sup.14, wherein, PA1 X: an oxygen atom or a group represented by a formula NR.sup.4, PA1 R.sup.1 : a hydrogen atom, a hydroxyl group or a triazolyl group, with the proviso that X may be a bond when R.sup.1 is a triazolyl group, PA1 R.sup.2 : a hydrogen atom, a nitro group, a halogeno-lower alkyl group, a cyano group, an amino group, a mono- or di-lower alkylamino group or a halogen atom, PA1 R.sup.3 and R.sup.4 : may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, PA1 n: 0, 1 or 2, PA1 m: an integer of 2 to 6, and PA1 p: an integer of 1 to 6) or a pharmaceutically acceptable salt thereof. The compound of the present invention has a characteristic from the viewpoint of its chemical structure that it always has a ##STR6## group at the 1- or 4-position of the nucleus of the 7- or 6-imidazole-substituted quinoxalinedione.
a) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] receptor PA2 b) kainate receptor PA2 (2) a lower alkyl group or a lower alkoxy group, wherein these groups may be substituted with a halogen atom(s), a carboxy group(s) or an aryl group(s), or PA2 (3) a lower alkoxycarbonyl group or a phenyloxy group which may be substituted with a carboxy group, PA2 R.sup.2 represents a hydrogen atom or --(CH.sub.2).sub.q --R.sup.3, PA2 R.sup.3 represents a hydrogen atom, a hydroxy group, a C.sub.1 -C.sub.6 alkoxy group or NR.sup.15 R.sup.16, PA2 n, m and q are respectively 0, 1, 2 or 3, PA2 Z represents POXY, OPOXY, OR.sup.17, NR.sup.18 R.sup.19, NH--COR.sup.20, NH--SO.sub.2 R.sup.21, SO.sub.2 R.sup.22, SO.sub.2 R.sup.23, a halogen atom, a cyano group or a tetrazole group, R.sup.12, R.sup.13, R.sup.17 and R.sup.23 respectively represent a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group and R.sup.14 represents H or a C.sub.1 -C.sub.6 alkyl group which is substituted 1 to 3 times with halogen atoms or unsubstituted, PA2 R.sup.20 and R.sup.21 respectively represent a C.sub.1 -C.sub.6 alkyl group or a phenyl or a heteroaryl group which is substituted or not substituted with a halogen atom and R.sup.22 represents a hydroxy group, a C.sub.1 -C.sub.4 alkoxy group or NR.sup.24 R.sup.25, PA2 R.sup.9 and R.sup.10 may be the same or different from each other and each represents a hydrogen atom, a CO-C.sub.1 -C.sub.6 alkyl group, a phenyl group or a C.sub.1 -C.sub.6 alkyl group, wherein these groups may be substituted with a C.sub.1 -C.sub.4 alkoxy or an amino group optionally mono- or di-substituted with a C.sub.1 -C.sub.4 alkyl or together with the nitrogen atom may form a 5- to 7-membered saturated heterocycle optionally having another N atom, S atom or O atom and may be substituted or an unsaturated 5-membered heterocycle which has 1 to 3 N atoms and may be substituted, and PA2 R.sup.24 and R.sup.25 may be the same or different from each other and each represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, or together with the nitrogen atom may form a 5- to 7-membered saturated heterocycle optionally having another oxygen atom, sulfur atom or nitrogen atom and may be substituted, and represents an isomer or a salt thereof (see descriptions in the following patent publication for the meaning of other symbols)] (International Patent Publication WO 94/25469 (to be referred to as reference 2 hereinafter)), and other compounds described in International Patent Publication WO 92/07847 and International Patent Publication WO 93/08173.
The compound of the present invention has glutamate receptor antagonism (particularly, AMPA receptor antagonism), kainic acid neurotoxicity inhibition action and audiogenic seizure inhibition action, so that it is useful as an anti-ischemia drug or a psychotropic drug.
L-Glutamic acid and L-aspartic acid activate the aforementioned glutamate receptors and transmit excitation. Nervous disorders occur when an excess amount of NMDA, AMPA or kainic acid is allowed to act on nerves. It has been reported that 2-amino-5-phosphonovalerianic acid or 2-amino-7-phosphonoheptanoic acid as a selective antagonist against NMDA receptors is effective in nervous disorders induced by the action of NMDA and in experimental animal models suffering from epilepsy and cerebral ischemia (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1987); Science, 226, 850 (1984)).
It has been reported that NMDA receptors are allosterically regulated by glycine receptors (EJP, 126, 303 (1986)), and that a glycine receptor antagonist HA-966 is also useful in an experimental animal model suffering from cerebral ischemia (American Society for Neuroscience, 1989).
In addition, it has been reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline) which is a selective antagonist against the AMPA receptor is also useful in an experimental animal model suffering from cerebral ischemia (Science, 247, 571 (1990)).
On the other hand, it has been shown that all of the cloned non-NMDA receptors have affinity for kainic acid. Among these receptors, a receptor having low affinity for kainic acid (AMPA/kainate receptor) has been indicated to be related to the neuronal death at the time of ischemia such as cerebral infarction (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). This AMPA/kainate receptor has high affinity for AMPA too, but the binding sites of AMPA and kainic acid are not clear. However, it has been reported that AMPA and kainic acid show different electrophysiological responses to the AMPA/kainate receptor. It has been reported also that AMPA alone shows weak action in a neurotoxicity test which uses a neuronal culture system, but kainic acid induces by itself significant neuronal death in the test (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). In consequence, there is a possibility that a compound capable of showing kainic acid toxicity inhibition action in a neuronal culture system will strongly inhibit neuronal death induced by excess excitement caused by glutamic acid at the time of ischemia.
Several compounds have been reported as quinoxalinedione derivatives which show NMDA-glycine receptor antagonism and/or AMPA receptor antagonism, such as a compound having a --A--COR.sup.2 group at the 1- or 4-position of the quinoxalinedione nucleus, represented by a formula ##STR2## (wherein each symbol has the following meaning: X: a nitrogen atom or a group represented by a formula CH,
with the proviso that a case in which R is an imidazolyl group, R.sup.1 is a cyano group, A is an ethylene group and R.sup.2 is a hydroxyl group is excluded) (International Patent Publication WO 96/10023 (to be referred to as reference 1 hereinafter)), a compound having a --(CH.sub.2).sub.n --CR.sup.2 H--(CH.sub.2).sub.m --Z group at the 1- or 4-position of the quinoxalinedione nucleus, represented by a formula ##STR3## [wherein, R.sup.1 represents --(CH.sub.2).sub.n --CR.sup.2 H--(CH.sub.2).sub.m --Z,